Effects of postnatal interventions for the reduction of ... · Effect of postnatal MTCT interventions on infant growth and non-HIV infections Compared to infant formula, breast milk

Review article

Effects of postnatal interventions for the reduction of vertical

HIV transmission on infant growth and non-HIV infections:

a systematic review

Moleen Zunza§,1, Gareth D Mercer2, Lehana Thabane3,4, Monika Esser5 and Mark F Cotton1

§Corresponding author: Moleen Zunza, Francie van Zijl Drive, Tygerberg 7505, South Africa. Tel: �27 73 376 4624. ([email protected])

Abstract

Introduction: Guidelines in resource-poor settings have progressively included interventions to reduce postnatal HIV

transmission through breast milk. In addition to HIV-free survival, infant growth and non-HIV infections should be considered.

Determining the effect of these interventions on infant growth and non-HIV infections will inform healthcare decisions about

feeding HIV-exposed infants. We synthesize findings from studies comparing breast to formula feeding, early weaning to

standard-duration breastfeeding, breastfeeding with extended antiretroviral (ARV) to short-course ARV prophylaxis, and

alternative preparations of infant formula to standard formula in HIV-exposed infants, focusing on infant growth and non-HIV

infectious morbidity outcomes. The review objectives were to collate and appraise evidence of interventions to reduce postnatal

vertical HIV transmission, and to estimate their effect on growth and non-HIV infections from birth to two years of age among

HIV-exposed infants.

Methods: We searched PubMed, SCOPUS, and Cochrane CENTRAL Controlled Trials Register. We included randomized trials

and prospective cohort studies. Two authors independently extracted data and evaluated risk of bias. Rate ratios and mean

differences were used as effect measures for dichotomous and continuous outcomes, respectively. Where pooling was possible,

we used fixed-effects meta-analysis to pool results across studies. Quality of evidence was assessed using the GRADE approach.

Results and discussion: Prospective cohort studies comparing breast- versus formula-fed HIV-exposed infants found

breastfeeding to be protective against diarrhoea in early life [risk ratio (RR)�0.31; 95% confidence interval (CI)�0.13 to

0.74]. The effect of breastfeeding against diarrhoea [hazard ratio (HR)�0.74; 95% CI�0.57 to 0.97] and respiratory infections

(HR�0.65; 95% CI�0.41 to 1.00) was significant through two years of age. The only randomized controlled trial (RCT) available

showed that breastfeeding tended to be protective against malnutrition (RR�0.63; 95% CI�0.36 to 1.12). We found no

statistically significant differences in the rates of non-HIV infections or malnutrition between breast-fed infants in the extended

and short-course ARV prophylaxis groups.

Conclusions: Low to moderate quality evidence suggests breastfeeding may improve growth and non-HIV infection outcomes of

HIV-exposed infants. Extended ARV prophylaxis does not appear to increase the risk for HIV-exposed infants for adverse growth

or non-HIV infections compared to short-course ARV prophylaxis.

Keywords: postnatal interventions; HIV; children; growth; non-HIV infections; breast milk.

To access the supplementary material to this article please see Supplementary Files under Article Tools online.

Received 8 September 2013; Revised 2 November 2013; Accepted 27 November 2013; Published 20 December 2013

Copyright:– 2013 Zunza M et al; licensee International AIDS Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution

3.0 Unported (CC BY 3.0) License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium,

provided the original work is properly cited.

IntroductionHIV infection among children is a public health concern

especially in poorly resourced countries [1]. Most children

acquire HIV infection through mother-to-child transmission

(MTCT) [2]. Approximately 2.5 million children are living

with HIV/AIDS worldwide [3]. Although the proportion of

HIV-attributable death among children less than five years of

age is declining worldwide, HIV/AIDS is still a leading cause

of premature death in Southern African children [4]. In the

absence of antiretroviral (ARV) treatment, one third of HIV-

infected children die by one year of age and about 50%

by two years of age [4]. Infectious diseases and nutritional

complications are the predominant underlying causes of

mortality in these children [4].

HIV may be vertically transmitted in pregnancy, labour,

delivery, or through breast milk. Without interventions, 15�30% of infants are vertically infected; breastfeeding increases

the risk to 20�45% [5]. Strategies to reduce postnatal vertical

transmission of HIV focus on reducing transmission through

breast milk. HIV-positive mothers in high-income countries

Zunza M et al. Journal of the International AIDS Society 2013, 16:18865

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are recommended to completely avoid breastfeeding [6].

However, in poorly resourced countries where formula feed-

ing does not generally meet AFASS criteria (Acceptable,

Feasible, Affordable, Sustainable, and Safe), avoiding breast-

feeding increases the risks of infant mortality and infectious

morbidity [7].

Description of the intervention

The efficacy of ARV regimens in reducing HIV vertical

transmission through breast milk has been demonstrated

in several randomized controlled trials (RCTs) [8�11], theseinterventions have since been incorporated into the World

Health Organization (WHO) guidelines on infant feeding by

HIV-positive mothers [12].

WHO 2013 prevention of MTCT (PMTCT) guidelines re-

commend that all HIV-positive pregnant women receive

highly active ARV treatment (HAART), until at least one week

after cessation of breastfeeding or after delivery when formula

feeding, but should preferably be continued as lifelong

therapy regardless of CD4 count [12]. Mothers with CD4

count 5500cells/mm3 orWHO clinical stage 3 or 4 disease are

recommended to continue lifelong ARVs. HIV-exposed in-

fants on breast milk are recommended to receive once-daily

nevirapine (NVP) prophylaxis until they are fully weaned.

Formula-fed infants should receive 4�6 weeks of daily NVP ortwice-daily zidovudine (ZDV) [12].

Effect of postnatal MTCT interventions on infant growth

and non-HIV infections

Compared to infant formula, breast milk protects against

gastrointestinal and respiratory tract infections and improves

overall survival [13]. Breastfeeding also promotes optimal

child growth until two years of age [14].

ARVs drugs minimize postnatal HIV transmission through

breast milk by reducing breast milk viral load. As ARVs have

clinical and laboratory adverse effects, their safety in HIV-

exposed children should be considered. Baroncelli et al.

reported a high risk of anaemia in HIV-exposed infants

exposed to HAART with ZDV alone compared to HAART

without ZDV, which disappeared at one month of life [15].

Grade 3�4 hepatoxicity was reported in infants exposed to

NVP for at least five days [16]. Neonatal exposure to lopinavir/

ritonavir (LPV/r) has been associated with cardiac toxicity

and adrenal dysfunction [17]. Lamivudine exposure is safe in

HIV-exposed infants [18]. While side effects would not negate

the benefits of ARVs in preventing HIV transmission, it is

important for health policy makers to have accurate estimates

of the anticipated risks of such effects when introducing these

interventions into clinical practice.

Why it is important to do this review

A Cochrane review appraised evidence for the efficacy of

postnatal HIV PMTCT interventions in preventing HIV trans-

mission, and improving HIV-free survival [19]. However, in

addition to their efficacy in preventing HIV transmission, policy

makers should consider the effects of these interventions on

infant growth and susceptibility to non-HIV infections.

Contradictory findings of the effects of different postnatal

PMTCT interventions on infant growth and non-HIV infec-

tious morbidity were reported in clinical trials and observa-

tional studies; therefore the true effects of the interventions

on these outcomes are uncertain. To inform decision-making

about HIV PMTCT recommendations, this review aims to

synthesize findings from studies comparing the effects of

different postnatal interventions for PMTCT of HIV on infant

growth and non-HIV infections, with follow-up periods of

between 3 and 24 months of age.

Objectives

To collate and appraise evidence of interventions to re-

duce postnatal vertical HIV transmission in HIV-exposed

infants, and estimate their effect on (1) growth from birth to

two years of age (primary objective) and (2) non-HIV infections

from birth to two years of age (secondary objective).

MethodsCriteria for considering studies for this review

Studies

. RCTs of postnatal interventions to prevent vertical

transmission of HIV, which included the assessment of

infant growth or non-HIV infections.

. RCTs assessing the effect of established postnatal

interventions for prevention of vertical transmission

of HIV on infant growth or on HIV infections.

. Cohort studies were also included if the interven-

tion (e.g. mode of feeding) could not be ethically

randomized.

Participants

HIV-positive mothers and their infants.

Interventions

Intervention aimed at reducing HIV vertical transmission.

Primary outcomes

. Weight-for-age (WAZ), weight-for-length (WLZ), length-

for-age (LAZ), and head circumference-for-age (HCA)

z-scores and malnutrition.

. Non-HIV infections, e.g. respiratory tract infections,

gastrointestinal infections.

Search methods for identification of studies

Electronic searches

Search strategies developed by The Cochrane Collaboration

HIV/AIDS Review group were used to search for studies [19].

PubMed (24 April 2013), SCOPUS (24 April 2013), and

Cochrane CENTRAL Controlled Trials Register (11 March

2013) were searched without language, time or publication

status restrictions (Supplementary file). Dates indicate the

timewhen searches were last performed in each database.The

reference lists of included studies were searched for studies.

Data collection and analysis

Selection of studies

Two reviewers (MZ and GM) independently reviewed ab-

stracts of electronic search results. Full texts of potentially

relevant articles were retrieved and independently examined

for eligibility.



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Data extraction

The following data were independently extracted in dupli-

cate: study design, study duration, methodological quality,

study interventions, and outcomes. Discrepancies were

resolved through discussion.

Assessment of risk of bias in included studies

The Cochrane Collaboration’s risk of bias tool was used to

assess the methodological quality of each selected study [20].

Two authors (MZ and GM) independently assessed the risk

of bias. The following domains were assessed: sequence

generation; allocation concealment; blinding of participants,

personnel, and outcome assessors; whether incomplete out-

comes data were adequately addressed; selective reporting;

and other bias.

ClinicalTrial.gov and Current Controlled trial registries

were searched for protocols of included studies. If the

protocol was unavailable, the methods and results sections

were compared to assess the potential for selective report-

ing bias.

Measures of treatment effect

When included publications presented summary data sepa-

rately for each intervention group, we calculated risk ratios

(RR) for binary outcomes and mean differences (MD) for

continuous outcomes, and associated 95% confidence inter-

vals (CI). Otherwise we have directly presented the effect

estimates [RR, hazard ratio (HR), and odds ratios (OR)]

reported in the publications.

For infectious morbidity events, we assumed that the

occurrence of each outcome per participant is a random

variable following a Poisson distribution. The normal approx-

imation to the Poisson distribution was used to calculate CI

for MD in the incidence of infectious morbidity outcomes.

The 95% CI for MD was calculated as:

k1 � k2

� �� 1:96�

ffiffiffiffiffiffiffiffiffiffiffiffiffik1

n1þ k2

n2

q, where k1 and k2 are esti-

mated average counts of a specific infection in Groups 1 and

2, and n1 and n2 are the numbers of infants with complete

follow-up data in each group [21]. Included studies did not

report results disaggregated by sex separately for each study

randomisation arm. Therefore, we could not extract study

results disaggregated by sex in this review.

Unit of analysis issues

Repeated observations on participants. When results

were presented for more than one time point, the following

approaches were used to obtain single effect measures:

For infectious events, we computed the total number

of events experienced during the entire follow-up period for

each intervention group. For growth outcomes, summary

data were extracted at the longest follow-up time point.

Multiple intervention groups. Experimental intervention

groups deemed sufficiently comparable were combined for

pairwise comparison with the control group. For dichotomous

outcomes, sample size and outcome events were summed

across combined groups. For continuous outcomes, means

and standard deviations (SD) were combined using the

following formulas [20]:

where N1, M1 and SD1 are sample size, mean and standard

deviation of Group 1, N2, M2, SD2 are the corresponding

values of Group 2.

Studies using a factorial design. One report was from a

trial that used a factorial design [11]. We only report on

the effect of ARV interventions in this review. Reports of the

study did not suggest an important interaction between the

two interventions.

Dealing with missing data

Authors of 12 studies were contacted for missing infor-

mation; the requested information being obtained for six

studies. The potential impact of missing data was considered

during risk of bias assessment. Meta-analysis was repeated,

excluding studies with attrition rates �20% to assess the

robustness of the results to missing data, and both estimates

are presented.

Assessment of heterogeneity

Substantial statistical heterogeneity was defined as an I2

statistic �50% [20].

Assessment of publication bias

Too few studies were included in each comparison to enable

an investigation of publication bias.

Data synthesis

Fixed-effects meta-analysis using the Mantel-Haenszel method

for dichotomous outcomes and the inverse-variance

method for continuous outcomes were used to pool results

across studies [20]. Where meta-analysis was inappropriate,

individual study results were reported separately. Review

Manager 5.1 was used for analysis.

Quality of evidence

The Grades of Recommendation Assessment, Development

and Evaluation (GRADE) approach was used to rate quality

SD ¼

ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiN1 � 1ð ÞSD2

1 þ N2 � 1ð ÞSD22 þ N1N2

N1þN2M2

1 þM22 � 2M1M2ð Þ

N1 þN2 � 1

vuut

Mean ¼ N1M1 þN2M2

N1 þN2



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of evidence [22]. In evaluating the quality of RCT evidence,

we considered the following in whether to downgrade the

quality of evidence: methodological limitations, inconsistency

in study results, indirectness, imprecision and publication

bias. For observational studies, we considered the following

factors in determining whether to upgrade the quality of

evidence: large observed effect and whether plausible

confounding would change the intervention effect. Our

ratings for the breastfeeding versus formula feeding and

the breastfeeding with extended versus short-course ARV

prophylaxis comparisons are presented in Tables 1 and 2,

respectively.

ResultsIncluded studies

We identified 14 reports from seven RCTs and three prospec-

tive cohort studies (Figure 1) conducted in: South Africa (3),

Zambia (1), Malawi (1), USA and Brazil (1), Cote d’lvoire (1),

Tanzania (1), Kenya (1), Burkina Faso, Kenya and South Africa

(1) and South Africa, Tanzania, Uganda and Zimbabwe (1)

(Supplementary file). Ten studies were excluded on review

of full articles (Supplementary file).

Types of interventions

Table 3 summarizes the studies included and outcomes

assessed under each comparison.

Risk of bias in included studies

The risk of bias summary presents authors’ judgments on risk

of bias in each domain for each study separately (Figure 2),

while the risk of bias graph presents the risk of bias in each

domain as a percentage across all included studies (Figure 3).

A summary of our findings on study methodological quality

for each domain follows below.

Allocation (selection bias)

Random sequence generation was adequate in 10 studies

[9,11,23�30]. The method of sequence generation was not

reported in one study [31]. Risk of bias was high for three

observational studies because participants self-selected into

comparison groups [32�34].Methods of allocation concealment were adequate in

10 studies [9,11,23�27,29�31]. One study did not report how

treatment allocation was concealed [28]. The risk of bias

in this domain was high for the three observational studies

[32�34].

Blinding (performance bias and detection bias)

Participants and personnel (performance bias). Seven

studies were assessed as having low risk of participant

performance bias [9,11,24,26,27,30,31]. Five studies were at

high risk because participants were unblinded and it was felt

that knowledge of their intervention allocation, rather than

the intervention itself, could have affected participants’ out-

comes [23,25,28,33,34]. Two studies were unclear on whether

participants were blinded [29,32]. Risk of personnel perfor-

mance bias was low in eight studies [9,11,23,24,26,27,30,31].

Two studies were at high risk because personnel may have

treated participants differently through knowing their inter-

vention allocation, thereby influencing the outcomes [25,33].

It was unclear in four studies whether personnel were blinded

[28,29,32,34].

Outcome assessment (detection bias). Risk of detec-

tion bias was judged to be low in 10 studies [9,11,23�27,31,33,34]. One study was at high risk because outcomes were

ascertained through participants’ verbal reports and outcome

definitions were relatively subjective [28]. It was unclear

whether outcome assessors were blinded in three studies

[29,30,32].

Incomplete outcome data (attrition bias)

Seven reports with an attrition rate below 20% were judged to

have low risk of attrition bias [9,11,27�30,33]. Five reports

were judged high risk [23,26,31,32,34], and two studies were

unclear [24,25].

Selective reporting (reporting bias)

Protocols were available for five studies [9,11,23,27,30].

Nine reports were at low risk of reporting bias [11,25�30,32,34]. Three reports were at high risk, because either

not all study results were reported at pre-specified time

points or the reported outcome was not pre-specified in the

protocol [9,23,24]. Risk of bias due to selective reporting was

unclear in two studies [31,33].

Table 1. Breastfeeding compared to formula feeding for HIV-exposed infants

Outcomes Relative effect (95% CI) Number of participants (studies) Quality of the evidence (GRADE)

Malnutrition RCT RR 0.63 (0.36 to 1.12) 371 (1) �� lowa,b

Diarrhoea ‘‘Cohort study, effect

up to two years of age’’

HR 0.74 (0.57 to 0.97) 557 (1) �� moderatea,c

Diarrhoea ‘‘Cohort study, effect

up to three months of age’’

RR 0.31 (0.13 to 0.74) 127 (1) �� lowc,d

Respiratory infections RCT HR 1 (0.9 to 1.11) 371 (1) �� lowa,b

Respiratory infections Cohort HR 0.60 (0.36 to 0.98) 557 (1) �� moderatec

Diarrhoea RCT HR 1.11 (0.91 to 1.43) 371 (1) �� lowa,b

aStudy had some methodological limitations, bwide confidence interval and fails to exclude the null effect, cobserved breastfeeding effect was

considered clinically important, dsample size was too small. RR: Risk ratio; HR: Hazard ratio.



4





Other sources of bias

Nine studies were judged low risk of other bias [9,25�30,32,33]. One study was at high risk; the Data Safety

Monitoring Board recommended enrolment of controls be

stopped early because of an apparent intervention benefit

[11]. Risk of other bias was unclear in four studies; either

baseline characteristics were not compared between study

arms, there was a potential for misclassification of expo-

sure status or the role of the funder was not described

[23,24,31,34].

Effects of interventions

Except where specified, results are from combined data from

HIV-infected and HIV-uninfected infants. Wherever publica-

tions presented findings separately for HIV-uninfected infants

we report these. For characteristics of included studies, see

Supplementary file.

1. Breastfeeding versus formula feeding

One RCT [28] and three prospective cohort studies [32�34]compared growth and non-HIV infections outcomes between

breast- and formula-fed HIV-exposed infants. We report the

RCT and cohort studies separately.

Mbori-Ngacha et al. randomly assigned mother-infant pairs

to breast or formula-feeding groups [28]. Cumulative HIV-

infection rates by two years of age were 37% and 21%,

respectively.

Becquet et al. compared infants whose mother chose

breastfeeding with rapid transition to formula feeding after

four months of age to infants whosemothers chose exclusively

formula feeding [32]. HIV transmission rates at 18 months

were 5% and 1% among breast- and formula-fed infants,

respectively.

Kindra et al. compared outcomes of infants whose

mothers elected to either breastfeed or formula feed. By

six weeks of age, HIV transmission rates were 7.9% and

4% among breast- and formula-fed infants, respectively

[33].

Venkatesh et al. compared rates of infant hospitalizations

associated with infectious morbidity among infants whose

mothers elected to breastfeed or formula feed [34]. They

documented HIV transmission rates of 18.4% and 13.2%

among breast- and formula-fed infants, respectively by three

months.

Outcomes

Growth

Kindra et al. found no difference in z-scores between breast-

and formula-fed infants at nine months of age [33].

Malnutrition

Mbori-Ngacha et al. defined malnutrition as a weight-for-

height z-score value 2 SD below the mean. Becquet et al.

defined malnutrition as an observation of either no change or

a decrease in anthropometric measurements between study

visits. Neither study found a statistically significant difference

in malnutrition risk between breast- and formula-fed infants

Table 2. Breastfeeding with extended ARV compared to breastfeeding with short-course ARV prophylaxis for HIV-exposed infants

Illustrative comparative risksa (95% CI)

Assumed risk Corresponding risk

Outcomes

Breastfeeding with

short-course ARVs

Breastfeeding with

extended ARVs

Relative effect

(95% CI)

Number of

participants (studies)

Quality of the

evidence (GRADE)

Study population

Growth faltering 32 per 1000 36 per 1000 (27 to 48) RR 1.12

(0.83 to 1.5)

5719 (3) ��

moderateb,c

Pneumonia The average incidence of

pneumonia ranged across

control groups from 0.03

to 0.11

The average incidence of

pneumonia in the intervention

groups was 0.01 lower (0.02

lower to 0.00 higher)

6437 (4) ��

moderateb,d

Meningitis The average incidence of

meningitis ranged across

control groups from 0.0089

to 0.0147


meningitis in the intervention

groups was 0 higher (0.01 lower

to 0.00 higher)

4914 (2) �� lowb,e

Gastroenteritis The average incidence of

gastroenteritis ranged across

control groups from 0.02 to

0.07


gastroenteritis in the

intervention groups was 0.01

higher (0.01 lower to 0.02

higher)

6437 (4) ��

moderateb,c

The assumed risk was based on the mean control group risk if there was one study included or otherwise, on mean range in control group risk

across studies. aThe corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the

intervention (and its 95% CI). bThere were too few studies to assess publication bias, cCI failures to exclude appreciable harm, dpoint estimates

vary widely, ethere were very few events. CI: Confidence interval; RR: Risk ratio.



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(RR�0.63; 95% CI�0.36 to 1.12) and (HR�1.35; 95%

CI�0.93 to 2.0) [28,32].

Respiratory tract infections

Mbori-Ngacha et al. do not describe how upper respiratory

tract infections were defined [28].The trial found no difference

in rates of respiratory infections between breast- and formula-

fed infants (HR�1.00; 95% CI�0.90 to 1.11) [28].

Becquet et al. defined acute respiratory infection as cough,

fever, and focal pulmonary findings [32]. Venkatesh et al. used

WHO International Classification of Disease (ICD-10) criteria

to classify respiratory infections associated with hospitali-

zations [34]. The pooled estimate from these observational

studies suggests a lower incidence of respiratory infections in

breast than formula fed infants (HR�0.65; 95% CI�0.41

to 1.00) [32,34]. After adjusting for HIV status, breast-fed

infants were 40% less likely to develop respiratory infections

(HR�0.60; 95% CI�0.36 to 0.98) [32].

Diarrhoea

Diarrhoea was defined as the passage of three or more

watery stools per 24-hour period for at least two days.

Mbori-Ngacha et al. found no difference over two years

between breast- and formula-fed infants either when includ-

ing both HIV-infected and HIV-uninfected infants (HR�1.11;

95% CI�0.91 to 1.43) or in HIV-uninfected infants alone

(HR�1.11; 95% CI�0.83 to 1.43) [28]. Venkatesh et al.

reported similar findings (HR�0.50; 95% CI�0.15 to 1.70)

as Mbori-Ngacha et al. Becquet et al. and Kindra et al. differ

from Mbori-Ngacha et al. and Venkatesh et al. Both studies

found that breast-fed infants were at lower risk for diarrhoea

(RR�0.31; 95% CI�0.13 to 0.74) [33], the risk was signi-

ficantly lower for breast-fed infants after adjusting for HIV

status (HR�0.74; 95% CI�0.57 to 0.97) [32].

2. Breastfeeding with extended ARV prophylaxis versus

short-course ARV prophylaxis

A clinical adverse event is defined as any health-related

reaction or effect experienced by a study participant. Serious

clinical adverse events (SAEs) in infants were assessed as

safety endpoints in studies comparing differing postnatal

ARV prophylaxis. Five studies compared the incidence of

SAEs between infants exposed to different combinations of

extended and short-course ARV prophylaxes during breast-

feeding [9,11,26,27,30]. We use the term ‘‘extended ARV

prophylaxis’’ to refer to interventions involving ARVs given for

longer duration than the (short-course) peri-partum prophy-

laxes that were standard of care at the time the studies were

conducted. Important assumptions were made for interven-

tions in this comparison. First, Jamieson et al. and the Kesho

Bora Study included maternal ARV interventions in their

studies. Since mothers were breastfeeding while receiving

the intervention, infants would be ingesting ARVs in breast

milk. On this basis, we felt these interventions could reason-

ably be compared with ARV interventions administered

directly to infants. This assumption is supported by findings

of Shapiro et al., that concentrations of NVP, lamivudine and

ZDV in breast milk of HIV-positive women receiving HAART

are similar to or higher than their serum concentrations,

and that infant serum NVP concentrations were sufficient to

inhibit HIV-1 replication [35]. Second, the studies by Jamieson

et al. and Kumwenda et al. each tested two extended ARV

regimens against a standard short-course regimen. We felt

that the two extended ARV interventions in each study were

sufficiently similar to combine the results for comparison with

the short-course ARV group.

Four studies [9,11,27,30] used standard Division of AIDS

toxicity tables to grade the severity of SAEs. One study [26]

used the WHO ICD-10 criteria. All five studies reported rates

of SAEs without stratifying by infants’ HIV status.

Figure 1. Flow diagram of screening process.



6



Coovadia et al. randomly assigned infants who had

received six weeks of once-daily NVP to continue a once-

daily NVP prophylaxis or placebo until six months of age [30].

Infants were followed-up until 18 months of age. At 12

months of age HIV transmission rates were 3.6% in the

placebo group and 2.8% in the NVP group.

Gray et al. compared ZDV given to infants for the first

six weeks of life to single dose (sd) NVP at delivery [26].

Cumulative HIV transmission rates at 12 weeks were 14.3%

in the sd NVP group and 18.1% in the ZDV group.

Jamieson et al. compared a control group of mothers given

sd NVP during labour or at delivery, and mothers and infants

receiving ZDV and lamivudine for one week, to two extended

ARV groups: postnatal either the mothers received HAART

or infants received daily NVP until 28 weeks of age [11].

At 48 weeks of follow-up, HIV transmission rates were 7%

in the control group and 4% in both extended ARV groups.

We combined the extended ARV groups to allow pairwise

comparison with the control group.

In the Kesho Bora Study [27] mothers received HAART

until weaning or a maximum of 6.5 months post-partum

(extended ARV group) or ZDV during pregnancy plus sd

NVP at onset of labour (short-course ARV group) [27]. By one

year of age 5.4% of infants in the extended ARV group

became HIV-infected compared to 9.5% in short-course

ARV group.

Kumwenda et al. compared sd NVP and ZDV given to

infants for the first week of life (control group) to 14 weeks

of NVP (extended NVP group) or 14 weeks of NVP plus ZDV

(extended NVP plus ZDV group) [9]. At nine months of

Table 3. Summary of included studies and outcomes assessed for each comparison

Comparisons Studies (Sample size) Outcomes assessed Studies

Breastfeeding vs. Infant formula feeding 4 (1741) Malnutrition

Growth

Respiratory tract infections

Diarrhoea

Becquet et al. 2007

Mbori-Ngacha et al. 2001

Kindra et al. 2012


Venkatesh et al. 2011


Becquet et al. 2007

Venkatesh et al. 2011

Kindra et al. 2012

Breastfeeding with extended ARV prophylaxis vs.

breastfeeding with short-course ARV prophylaxis

5 (7956) Growth faltering

Pneumonia

Gastroenteritis

Meningitis

Sepsis

Jamieson et al. 2012

Kesho Bora 2011

Kumwenda et al. 2008

Coovadia et al. 2012

Kesho Bora, 2011

Gray et al. 2005


Kesho Bora, 2011


Coovadia et al. 2012

Kesho Bora, 2011

Gray et al. 2005






Early cessation of breastfeeding vs. standard duration 2 (451) Growth

Prolonged diarrhoea

Arpadi et al. 2008

Fawzy et al. 2011

Chemically or biologically acidified infant formula vs.

standard infant formula

1 (132) Growth

Bronchopneumonia

Gastroenteritis

Velaphi et al. 2008

Concentrated infant formula vs. standard infant

formula

1 (1686) Growth Winter et al. 2009

Chemical acidified infant formula milk with or without

prebiotics and nucleotides

1 (84) Growth Cooper et al. 2010



7



age HIV transmission rates were 10.6%, 5.2% and 6.4% in the

control, the extended NVP and the extended NVP plus ZDV

groups, respectively. We combined the two extended ARV

groups for pairwise comparison with the control group.

Outcomes

Growth faltering

The risk of growth faltering was 12% higher in infants on

extended ARV prophylaxis than short-course ARV prophylaxis

(RR�1.12; 95% CI�0.83 to 1.50) [9,11,27] (Figure 4).

Pneumonia

The MD in incidence of pneumonia in the extended ARV

prophylaxis group was �0.01 (95% CI��0.02 to �0.00)

[9,11,26,27] (Figure 5).TheMDwas �0.02 (95% CI��0.03 to

�0.00) when we excluded the study with a high attrition rate.

Risk of pneumonia was similar between the groups in the

Coovadia study [30].

Meningitis

There was no difference in meningitis incidence between

extended and short-course ARV prophylaxis groups [9,11].

Gastroenteritis

There was no difference in rates of gastroenteritis between

extended and short-course ARV prophylaxis (MD�0.01; 95%

CI��0.01 to 0.02) [9,11,26,27] (Figure 6). Coovadia et al.

found no difference in risk of gastroenteritis between the two

groups (RR�0.90; 95% CI�0.61 to 1.33) [30].

Sepsis

Incidence of sepsis was similar between intervention groups

[9].

3. Early breastfeeding cessation versus standard duration

of breastfeeding

Two reports from a single RCT presented growth and diar-

rhoeal morbidity outcomes in HIV-exposed uninfected infants

whose mothers were randomly assigned to stop breastfeeding

at four months (intervention group) or to continue breastfeed-

ing for as long as they wished, with the median duration being

16.2 months (control group) [23,25]. HIV transmission rates

were 21.4% and 25.8% in the intervention and control groups,

respectively.

Outcomes

Growth

Weight-for-age z-scores at two years of age were similar

between infants stopping breastfeeding early compared to

continuing for a longer duration (MD�0.12; 95% CI��0.10

to 0.34) [23].

Prolonged diarrhoea

Diarrhoea lasting for at least seven days was defined as

prolonged [25]. During the 7�24 months age period, the

odds of having an episode of prolonged diarrhoea when

breastfeeding was stopped early were almost twice that of

breastfeeding for a longer duration (OR�1.70; 95% CI�1.28

to 2.26).

4. Chemically or biologically acidified formula versus

standard formula

Velaphi et al. compared infectious morbidity and growth

between HIV-exposed uninfected infants receiving chemically

or biologically acidified formula and those receiving standard

formula for the first four months [31].

Infants were randomly assigned to four groups:

1) Non-acidified (standard) whey-adapted starter formula

2) Chemically acidified standard formula, where acidifica-

tion was achieved through addition of L(�) lactic acid

3) Chemically acidified standard formula with Bifidobac-

terium lactis CNCM I-3446 added

4) Biologically acidified standard formula, where acidifica-

tion was achieved through bacterial fermentation

We combined the two chemically acidified formula groups

and the biologically acidified formula group for pairwise

comparison with the standard formula group.

Figure 2. Risk of bias for each domain per study.



8



Outcomes

Growth

Z-scores were calculated based on growth charts from the

Centre for Disease Control and Prevention (CDC) and were

presented up to four months of age. Head circumference-for-

age z-scores were significantly higher in infants who received

acidified formulas compared to infants who received stan-

dard formula (MD�0.31; 95% CI�0.15 to 0.48). The study

found no significant differences in WLZ-scores (MD�0.09;

95% CI��0.16 to 0.34), LAZ-scores (MD�0.08; 95%

CI��0.15 to 0.30) and WAZ-scores (MD�0.18; 95%

CI��0.05 to 0.41) between study groups.

Bronchopneumonia and gastroenteritis

The authors do not describe how infectious outcomes were

defined. Incidence of bronchopneumonia (MD 0.12; 95%

CI��0.03 to 0.27) and gastroenteritis (MD �0.07; 95%

CI��0.17 to 0.02) between birth and six months of age were

similar between infants on acidified formula and those on

standard formula.

5. Concentrated formula versus standard formula

Winter et al. assessed growth in HIV-exposed uninfected

infants randomly assigned to receive either 87 kcal/100mL

concentrated infant formula or 67 kcal/100mL standard

formula [29].

Outcomes

Growth

Z-scores were calculated using the 2000 National Centre

for Health Statistics paediatric growth references. Mean

WAZ-scores were significantly higher for infants on concen-

trated formula than standard formula (MD�0.12; 95%

CI�0.04 to 0.20). We found no significant differences in

WLZ-scores (MD�0.11; 95% CI��0.01 to 0.23), LAZ-

scores (MD�0.03; 95% CI��0.06 to 0.12), and head-

circumference-for-age z-scores (MD��0.03; 95% CI��0.11

to 0.05).

6. Chemically acidified formula with or without prebiotics

and nucleotides

Growth and infectious morbidity were compared in HIV-

exposed, uninfected infants on chemically acidified formula

alone and with prebiotics and nucleotides [24]. Infants were

randomly assigned to three study groups and followed-up

until six months of age:

1) Chemically acidified formula (control)

2) Chemically acidified formula with prebiotics (a blend of

short-chain and long chain fructo-oligosaccharides)

3) Chemically acidified formula with prebiotics and nu-

cleotides (a blend of cytidine, uridine, adenosine and

guanosine monophosphates)

Chemical acidification was achieved as in [31]. We combined

outcomes from infants in Groups 2 and 3 to allow pairwise

comparisons with Group 1.

Outcomes

Growth

Z-scores were calculated using the 2000 CDC growth charts.

The primary study report presented summary data and

Figure 4. Forest plot of breastfeeding with extended ARV prophylaxis vs. short-course ARV prophylaxis: Growth faltering.

Figure 3. Risk of bias graph for each domain across all studies.



9



corresponding 95% CIs in graph format. We estimated mean

z-scores and SDs from the graphs.

Mean WAZ-scores (MD�0.08; 95% CI��0.15 to 0.31)

and LAZ-scores (MD��0.14; 95% CI��0.39 to 0.1) were

similar in all groups.

DiscussionSummary of main findings

We reviewed findings from seven RCTs and three cohort

studies evaluating the effects of various postnatal interven-

tions for PMTCT of HIV.

From our meta-analysis, breastfeeding appears to decrease

the risk of respiratory infections by 35%, when infant feeding

mode is self-selected and when not considering infant HIV

status. However, this finding was not supported by the only

RCT reporting on this comparison. There is moderate quality

evidence that the risk of respiratory infection remains lower

(by 40%) in breast-fed infants through to two years of age,

after adjusting for infant HIV status [32].

The evidence from this review is inconsistent on the effect

of breast versus formula feeding on diarrhoeal morbidity.

In three observational studies, breastfeeding significantly

reduced the risk of diarrhoeal morbidity in early life [33,34],

and, of diminished magnitude until the second birthday [32].

We graded this evidence of moderate quality. A randomized

trial found no significant difference in diarrhoeal morbidity

between breast- and formula-fed infants up to two years

of age [28]. This trial was not powered to test equivalence of

diarrhoeal morbidity in the two arms. Therefore, it is impor-

tant to avoid interpreting the lack of statistical significance

as evidence of equivalent risk. Breastfeeding is expected to

reduce diarrhoea incidence. There are a few possible explana-

tions why this was not observed in this trial. HIV transmis-

sion was higher among breast-fed than formula-fed infants,

probably obscuring the protective effect of breastfeeding.

However, even when results from HIV-uninfected infants

were analysed separately, no significant difference was found.

A limitation of performing this type of sub-analysis is that the

comparison groups are no longer ‘‘as randomized,’’ therefore

not necessarily comparable in baseline characteristics, thus

possibly obscuring the true effect of breastfeeding. In our

opinion, the most likely explanation is that as 30% of mothers

assigned to the formula group had breastfed their infants [28],

some protective effect of breast milk occurred in the formula

group.

In the only RCT comparing breastfeeding versus formula

feeding, the risk of malnutrition was 37% lower in breast-fed

infants. Though not statistically significant, the reduction in

risk may be clinically important because the 95% CI includes

strongly protective values at the lower limit and excludes

values indicating appreciable harm from breastfeeding at the

upper limit. Also, high HIV transmission rates in breast-fed

infants would be expected to attenuate any protective effect

of breastfeeding, pulling the estimate towards the null.

On the other hand, high rates of non-compliance in the

formula-feeding group could be confounding this result. This

evidence is judged of low quality. Further research comparing

the nutritional outcomes of breast- versus formula-fed

infants of HIV-positive mothers is warranted.

We found moderate quality evidence that breastfeeding

with extended ARV prophylaxis is associated with fewer

pneumonia episodes compared to breastfeeding with short-

course ARV prophylaxis in HIV-exposed infants. The causal

explanation remains unclear. If evidence of this association

continues to accumulate, further investigation to explain the

underlying biological mechanisms should be prioritized.

However, high HIV transmission rates in infants on short-

course ARV prophylaxis, especially in studies contributing

substantial sample size to our meta-analysis [9,27], could

explain the higher incidence of pneumonia experienced by

infants in this group.

Our meta-analysis shows a modestly increased risk for

growth faltering among infants in the extended ARV group.

This estimate has a wide CI, which includes the null effect.

Figure 5. Forest plot of breastfeeding with extended ARV prophylaxis vs. short-course ARV prophylaxis: Pneumonia.

Figure 6. Forest plot of breastfeeding with extended ARV prophylaxis vs. short-course ARV prophylaxis: Gastroenteritis.



10



However, there is some evidence that infants exposed to ARV

therapy in utero, compared to postnatal ZDV, have reduced

growth up to two years of age [36]. Therefore, growth of

infants exposed to postnatal ARVs should be studied further.

We did not find the rates of any other SAEs to differ

significantly between infants in the extended and short-course

ARV prophylaxis groups. We do not believe that inadequate

follow-up explains the lackof observed differences. In addition,

with sample sizes of between 1898 and 5719 for different

outcomes, it seems reasonable to conclude that extended

ARV prophylaxis does not increase the risk for HIV-exposed

infants to experience non-HIV infections outcomes compared

to short-course ARV prophylaxis.

ConclusionsImplications for practice

Breastfeeding may reduce the risk of diarrhoeal morbidity,

respiratory tract infections and malnutrition compared to

formula feeding in HIV-exposed infants. Extended ARV

prophylaxis and formula feeding can effectively reduce or

prevent late postnatal transmission of HIV infection (19).

The magnitude of absolute benefit of breastfeeding com-

bined with extended ARV prophylaxis may be sufficient to

improve survival of children.

The benefits of breastfeeding with extended ARV prophy-

laxis must be weighed against the risk of HIV transmission

through breast milk when making decisions about feeding

HIV-exposed infants. Baseline risks, such as maternal viral

load, safety of ARVs and sustained adherence should also

influence decisions. Uptake of exclusive breastfeeding is

reportedly poor in most African settings [37,38]. Sub-optimal

infant feeding practices are likely to modify the effectiveness

of breastfeeding with ARV prophylaxis, especially in normal

practice settings. Continuous evaluation of these interventions

to determine whether their effectiveness remains clinically

important should be a priority as these interventions are

introduced into clinical practice.

Implication for research

Large prospective cohort studies with sufficient length of

follow-up are justified to investigate the effectiveness of

postnatal interventions for PMTCT of HIV in normal practice

settings. The studies should include infectious morbidity and

infant growth as primary outcomes. Effects of specific infant

formulas on growth require further evaluation.

Authors’ affiliations1Department of Paediatrics and Child Health, Children’s Infectious Disease

Clinical Research Unit, Stellenbosch University, Tygerberg, South Africa; 2MD/

PhD Program, Faculty of Medicine, University of British Columbia, Vancouver,

British Columbia, Canada; 3Department of Clinical Epidemiology and

Biostatistics, McMaster University, Hamilton, Ontario, Canada; 4Biostatistics

Unit/FSORC, St Joseph’s Healthcare Hamilton, Hamilton, Ontario, Canada;5Department of Pathology, Immunology Unit, NHLS, Stellenbosch University,

Tygerberg, South Africa

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

MZ: Contributed in conception and design of review, screened search results,

data extraction, analysis and interpretation, and writing of the manuscript.

GDM: Assisted in designing the review protocol, screened search results,

extracted data, rated evidence, and assisted with analysis and interpretation,

and writing of the manuscript. LT: Revised manuscript, gave input on statistical

analysis and interpretation. ME: Contributed in conception of review, edited

the manuscript and gave input on interpretation. MC: Contributed in

conception and design of review, edited the manuscript and gave input on

interpretation. All authors have read and approved the final manuscript.

Acknowledgements

The review authors thank Alvina Matthee for performing the electronic

database searches and authors of primary studies who provided requested

information.

Funding

This research has been supported by: The President’s Emergency Plan for AIDS

relief (PEPFAR) through HRSA under the terms of T84HA21652, Stellenbosch

University Faculty of Medicine and Health Sciences Clinical Research Grant,

South Africa Medical Research Council Self-Initiated Grant. GM is supported by

a CFRI-CIHR-UBC MD/PhD Studentship Award and a Canadian Institutes of

Health Research (CIHR) Vanier Canada Graduate Scholarship.

The funders had no role in study design, data extraction and analysis,

decision to publish, or preparation of the manuscript.

Disclaimer

The views expressed in this article are those of the authors and do not

necessarily reflect the view of the funders.

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Effects of postnatal interventions for the reduction of ... · Effect of postnatal MTCT interventions on infant growth and non-HIV infections Compared to infant formula, breast milk